Personalized, parcel-guided rTMS for the treatment of major depressive disorder: Safety and proof of concept.

BACKGROUND: Not all patients with major depressive disorder (MDD) benefit from the US Food and Drug Administration-approved use of repetitive transcranial magnetic stimulation (rTMS) at the dorsolateral prefrontal cortex. We may be undertreating depression with this one-size-fits-all rTMS strategy. METHODS: We present a retrospective review of targeted and connectome-guided rTMS in 26 patients from Cingulum Health from 2020 to 2023 with MDD or MDD with associated symptoms. rTMS was conducted by identifying multiple cortical targets based on anomalies in individual functional connectivity networks as determined by machine learning connectomic software. Quality of life assessed by the EuroQol (EQ-5D) score and depression symptoms assessed by the Beck Depression Inventory (BDI) were administered prior to treatment, directly after, and at a follow-up consultation. RESULTS: Of the 26 patients treated with rTMS, 16 (62%) attained remission after treatment. Of the 19 patients who completed follow-up assessments after an average interval of 2.6 months, 11 (58%) responded to treatment and 13 (68%) showed significant remission. Between patients classified with or without treatment-resistant depression, there was no difference in BDI improvement. Additionally, there was significant improvement in quality of life after treatment and during follow-up compared to baseline. LIMITATIONS: This review is retrospective in nature, so there is no control group to assess the placebo effect on patient outcomes. CONCLUSION: The personalized, connectome-guided approach of rTMS is safe and may be effective for depression. This personalized rTMS treatment allows for co-treatment of multiple disorders, such as the comorbidity of depression and anxiety.

Improving quality of life post-tumor craniotomy using personalized, parcel-guided TMS: safety and proof of concept.

PURPOSE: Deficits in neuro-cognitive function are not uncommon for patients who have undergone surgical removal of brain tumors. Our goal is to evaluate the safety and efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) as a non-invasive tool for the treatment of neuro-cognitive dysfunctions following craniotomy. METHODS: We present a retrospective review of individualized rTMS in twelve patients from Cingulum Health from December 2019 to July 2021 who presented with neuro-cognitive deficits following craniotomy. Multiple cortical targets were selected based on the patient's neurological disorder, associated networks, and anomalies in the functional connectivity of the brain as determined by machine-learning. TMS treatment was performed for five consecutive days. EuroQol quality of life (EQ-5D), functional extremity scales, and neuropsychiatric questionnaires related to the patient's deficit were assessed prior to, after, and during two-month follow-up of rTMS treatment. RESULTS: Nine patients had unilateral functional deficits in either upper, lower, or both limbs. One patient reported post-operative depression, another experienced short term memory difficulties, and a third reported hypobulia. All twelve patients reported significantly improved EQ5D after rTMS treatment and during follow-up. More than half of the patients with lower and upper functional deficits had a 9-point improvement during follow-up. In the patient who developed depression, an 88% reduction in depressive symptoms based on the Beck's Depression Inventory (BDI) was observed during follow-up. No adverse events, such as seizures, occurred. CONCLUSION: The personalized functional connectivity approach to rTMS treatment may be effective and safe for patients with post-craniotomy neuro-cognitive dysfunction.

Transient receptor potential melastatin 3 dysfunction in post COVID-19 condition and myalgic encephalomyelitis/chronic fatigue syndrome patients.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multisystemic condition associated with post-infectious onset, impaired natural killer (NK) cell cytotoxicity and impaired ion channel function, namely Transient Receptor Potential Melastatin 3 (TRPM3). Long-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has resulted in neurocognitive, immunological, gastrointestinal, and cardiovascular manifestations recently recognised as post coronavirus disease 2019 (COVID-19) condition. The symptomatology of ME/CFS overlaps significantly with post COVID-19; therefore, this research aimed to investigate TRPM3 ion channel function in post COVID-19 condition patients. METHODS: Whole-cell patch-clamp technique was used to measure TRPM3 ion channel activity in isolated NK cells of N = 5 ME/CFS patients, N = 5 post COVID-19 patients, and N = 5 healthy controls (HC). The TRPM3 agonist, pregnenolone sulfate (PregS) was used to activate TRPM3 function, while ononetin was used as a TRPM3 antagonist. RESULTS: As reported in previous research, PregS-induced TRPM3 currents were significantly reduced in ME/CFS patients compared with HC (p = 0.0048). PregS-induced TRPM3 amplitude was significantly reduced in post COVID-19 condition compared with HC (p = 0.0039). Importantly, no significant difference was reported in ME/CFS patients compared with post COVID-19 condition as PregS-induced TRPM3 currents of post COVID-19 condition patients were similar of ME/CFS patients currents (p > 0.9999). Isolated NK cells from post COVID-19 condition and ME/CFS patients were resistant to ononetin and differed significantly with HC (p < 0.0001). CONCLUSION: The results of this investigation suggest that post COVID-19 condition patients may have impaired TRPM3 ion channel function and provide further evidence regarding the similarities between post COVID-19 condition and ME/CFS. Impaired TRPM3 channel activity in post COVID-19 condition patients suggest impaired ion mobilisation which may consequently impede cell function resulting in chronic post-infectious symptoms. Further investigation into TRPM3 function may elucidate the pathomechanism, provide a diagnostic and therapeutic target for post COVID-19 condition patients and commonalities with ME/CFS patients.

WAO-ARIA consensus on chronic cough - Part III: Management strategies in primary and cough-specialty care. Updates in COVID-19.

Background: Chronic cough management necessitates a clear integrated care pathway approach. Primary care physicians initially encounter the majority of chronic cough patients, yet their role in proper management can prove challenging due to limited access to advanced diagnostic testing. A multidisciplinary approach involving otolaryngologists and chest physicians, allergists, and gastroenterologists, among others, is central to the optimal diagnosis and treatment of conditions which underly or worsen cough. These include infectious and inflammatory, upper and lower airway pathologies, or gastro-esophageal reflux. Despite the wide armamentarium of ancillary testing conducted in cough multidisciplinary care, such management can improve cough but seldom resolves it completely. This can be due partly to the limited data on the role of tests (eg, spirometry, exhaled nitric oxide), as well as classical pharmacotherapy conducted in multidisciplinary specialties for chronic cough. Other important factors include presence of multiple concomitant cough trigger mechanisms and the central neuronal complexity of chronic cough. Subsequent management conducted by cough specialists aims at control of cough refractory to prior interventions and includes cough-specific behavioral counseling and pharmacotherapy with neuromodulators, among others. Preliminary data on the role of neuromodulators in a proof-of-concept manner are encouraging but lack strong evidence on efficacy and safety. Objectives: The World Allergy Organization (WAO)/Allergic Rhinitis and its Impact on Asthma (ARIA) Joint Committee on Chronic Cough reviewed the recent literature on management of chronic cough in primary, multidisciplinary, and cough-specialty care. Knowledge gaps in diagnostic testing, classical and neuromodulator pharmacotherapy, in addition to behavioral therapy of chronic cough were also analyzed. Outcomes: This third part of the WAO/ARIA consensus on chronic cough suggests a management algorithm of chronic cough in an integrated care pathway approach. Insights into the inherent limitations of multidisciplinary cough diagnostic testing, efficacy and safety of currently available antitussive pharmacotherapy, or the recently recognized behavioral therapy, can significantly improve the standards of care in patients with chronic cough.

Itch Beyond the Skin-Mucosal Itch.

Itch is a nociceptive sensation linked with reflexes and cognitive motor actions. We traditionally think of itch as a sensation of the skin related to allergy, an insect sting or interestingly, anxiety and frustration. Less understood and considered are the physiological processes involved in the itching sensation that occurs at mucosal and junctional dermal sites, which is extraordinary as from an evolutionary point of view these sites serve important guardian roles, rich in sensory nerves and inflammatory cells. Despite itch being an ancient reflex and evolutionarily conserved phenomenon, better clinical understanding of the nuances between sites of itch sensation may lead to improved clinical outcomes. This review invites readers to appreciate itch beyond the skin by highlighting several specific itch patterns-nasal, oral, auricular, vulvovaginal, anal, and perineal itch-the pathophysiological mechanisms that underlie them, the clinical patterns these may cause, and some unique treatments.

Oral antihistamine-decongestant-analgesic combinations for the common cold.

BACKGROUND: Although combination formulas containing antihistamines, decongestants and/or analgesics are sold over-the-counter (OTC) in large quantities for the common cold, the evidence of effectiveness is limited. OBJECTIVES: To assess the effectiveness of antihistamine-decongestant-analgesic combinations in reducing the duration and alleviating the symptoms of the common cold in adults and children. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, OLDMEDLINE (1953 to 1965), MEDLINE (1966 to November Week 3, 2011) and EMBASE (1990 to December 2011). SELECTION CRITERIA: Randomised controlled trials (RCTs) investigating the effectiveness of antihistamine-decongestant-analgesic combinations compared with placebo, other active treatment (excluding antibiotics) or no treatment in children and adults with the common cold. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and summarised data on general recovery, nasal obstruction, rhinorrhoea, sneezing, cough and side effects. We categorised the trials according to the active ingredients. MAIN RESULTS: We included 27 trials (5117 participants) of common cold treatments. Fourteen trials studied antihistamine-decongestant combinations; two antihistamine-analgesic; six analgesic-decongestant; and five antihistamine-analgesic-decongestant combinations. In 21 trials the control intervention was placebo and in six trials an active substance. Reporting of methods in most trials was poor and there were large differences in design, participants, interventions and outcomes. Pooling was only possible for a limited number of studies and outcomes.Antihistamine-decongestant: 12 trials. Eight trials report on global effectiveness, six could be pooled; n = 309 on active treatment, n = 312 placebo) the odds ratio (OR) of treatment failure was 0.27 (95% confidence interval (CI) 0.15 to 0.50); the number needed to treat for an additional beneficial outcome (NNTB) was four (95% CI 3 to 5.6). On the final evaluation day 41% of participants in the placebo group had a favourable response compared to 66% on active treatment. Of the two trials that were not included in the pooling, one showed some global effect, the other showed no effect.Antihistamine-analgesic: three trials. Two reported on global effectiveness, data from one study was presented. (n = 290 on active treatment, n = 292 ascorbic acid). The OR of treatment failure was 0.33 (95% CI 0.23 to 0.46) and the NNTB was 6.67 (95% CI 4.76 to 12.5). After six days of treatment 43% were cured in the control group and 70% in the active treatment group. The second study also showed an effect in favour of active treatment.Analgesic-decongestant: six trials. One trial reported on global effectiveness: 73% benefited compared with 52% in the control group (paracetamol) (OR 0.28, 95% CI 0.15 to 0.52).Antihistamine-analgesic-decongestant: Five trials. Four trials reported on global effectiveness, two could be pooled: global effect reported (less than one severity point on a four or five-point scale) with active treatment (52%) and placebo (34%); the OR of treatment failure was 0.47 (95% CI 0.33 to 0.67) and the NNTB was 5.6 (95% CI 3.8 to 10.2). Two other trials found no beneficial effect. Two other studies did not show any effect.Two studies with antihistamine-decongestant (113 children) could not be pooled. There was no significant effect of the active treatment.Adverse effects: the combination of antihistamine-decongestant had more adverse effects than the control intervention but the difference was not significant: 157/810 (19%) versus 60/477 (13%) participants suffered one or more adverse effects (OR 1.58, 95% CI 0.78 to 3.21). Analgesic-decongestant combinations had significantly more adverse effects than control (OR 1.71, 95% CI 1.23 to 2.37); the number needed to treat for an additional harmful outcome (NNTH) was 14. None of the other two combinations caused significantly more adverse effects. Antihistamine-analgesic: 11/90 with combination suffered one or more adverse effects (12%) versus 9/91 (10%) with control (OR 1.27, 95% CI 0.50 to 3.23). Antihistamine-analgesic-decongestant: in one study 5/224 (2%) suffered adverse effects with active treatment versus 9/208 (4%) with placebo. Two other trials reported no differences between treatment groups but numbers were not reported. AUTHORS' CONCLUSIONS: Current evidence suggests that antihistamine-analgesic-decongestant combinations have some general benefit in adults and older children. These benefits must be weighed against the risk of adverse effects. There is no evidence of effectiveness in young children.